Lung cancer is the leading cause of death in the United States. About 213,380 new cases of lung cancer will be diagnosed in 2008 accounting for over 160,390 deaths annually. Despite recent advances in treatment strategies, the overall 5-year survival rate of less than 16%. Therefore, novel therapies are urgently needed. Progress in understanding the "molecular drivers" of cancer has resulted in the testing of small molecule inhibitors and biologics for lung cancer, such as cetuximab, gefitinib, and erlotinib, all targeting the epidermal growth factor receptor (EGFR). Although the FDA approved EGFR inhibitors are being widely tested, a major clinical problem is the inability to demonstrate that the inhibitors targeted the tumors. Furthermore, the therapeutic effect produced by these inhibitors during and after treatment cannot be determined rapidly. Therefore, patients may continue for extended periods of time on an ineffective treatment. To overcome the current limitations of cancer treatment and improve the health, development and acceleration of the application of biomedical technologies such as nanotechnology and nanomaterials are warranted. Development of such technologies will provide a new paradigm for lung cancer treatment. Reports on nanoparticles that are useful either for molecular imaging, drug delivery, or therapy of cancer exist. However, development and testing of multifunctional nanoparticles that enables both molecular imaging and therapy of lung tumors have not been reported and is warranted. In the present application we propose to conduct pilot feasibility studies to test a novel tumor-targeted multifunctional nanoparticle using lung cancer as a model. Our nanoparticles are composed of a superparamagnetic iron (SPIO) core coated with gold creating an iron-oxide/gold hybrid useful for Magnetic Resonance Imaging (MRI) and optical imaging. The clinically approved anti-EGFR antibody (cetuximab) is decorated on the surface of gold nanoparticles that serves both as a targeting moiety and therapeutic agent. We hypothesize that our tumor-targeted multifunctional nanoparticles will selectively target EGFR-expressing tumor cells and produce a therapeutic effect that can be monitored by non-invasive imaging. To test our hypothesis we have identified two specific aims: Specific Aim 1: Molecular characterization of EGFR-targeted multifunctional nanoparticles against human lung cancer cells expressing EGFR at different levels and comparison with normal cells in vitro. Specific Aim 2: Test the in vivo efficacy of EGFR-targeted multifunctional nanoparticles against EGFR-positive and -negative lung tumor xenografts. The goals of the specific aims proposed in this application will be achieved by utilizing molecular, cellular and animal models. Results from the proposed feasibility studies will lead to advanced preclinical studies and finally translate to clinical testing of the tumor-targeted multifunctional nanoparticles for lung cancer treatment. Public Health Relevance: This novel and innovative study proposes to develop and test tumor-targeted gold-iron hybrid nanoparticles that have multifunctional properties useful for molecular imaging of and therapy of lung cancer. Our studies will lead to advanced preclinical studies and ultimately testing of these multifunctional nanoparticles in the clinic.